Men and women may differ in factors that reinforce smoking behavior: self-administration of nicotine per se is often less robust in women, women are less sensitive to many effects of nicotine, and nicotine replacement is less effective for smoking cessation in women. Nicotine therefore may be a less reinforcing consequence of tobacco smoking in women vs. men. Other results suggest that non-nicotine aspects of smoking (e.g. sensory effects) may be more reinforcing in women. In this revision of "Sex Differences in Nicotine Reinforcement: Human/Animal" (DA 12655), we will examine sex differences in the influence of nicotine and non-nicotine factors on self-administration (SA) behavior. A unique feature of this proposal is a parallel series of studies exploring these questions using an animal (rat) model of nicotine self-administration. Procedures in the human and animal lines of research will allow independent manipulation of nicotine and non-nicotine factors. Our specific aims are to: 1) Examine differences in smoking (human) or i.v. nicotine (rat) self-administration in females as a function of menstrual/estrus cycle phase and compare this SA behavior to males. Results will determine the influence of cycle phase on SA, which may help explain observed sex differences, and critically inform the design of all subsequent research in this project as to whether cycle phase must be controlled. 2) Examine sex differences in the influence of nicotine dose on SA behavior in humans and animals. Nicotine clearly is the primary psychoactive ingredient reinforcing smoking behavior. However, nicotine may be less important in regulating this behavior in females. We will explore this possibility by determining whether self-administration behavior is less affected by manipulations of nicotine dose in females. 3) Examine sex differences in the influence of non-nicotine, drug-related stimuli on SA in humans and animals. Males' behavior may be more tightly controlled by nicotine and females' relatively more influenced by non-nicotine cues accompanying drug. Results will determine the reinforcing effect of smoking stimuli that have been largely ignored in past human research and provide directions for future study of conditioned reinforcement of smoking. Findings will clarify whether, and to what extent, nicotine and non-nicotine factors differentially reinforce SA behavior in females versus males. Similarities between species would bolster the relevance of the animal findings for human smoking reinforcement and allow an animal model by which to subsequently (and more invasively) investigate mechanisms for these sex differences. Results will increase our understanding of tobacco dependence in women and suggest approaches to developing improved smoking cessation treatments for women, among other future directions. This program may also provide directions for the study of sex differences in pharmacological and non-pharmacological reinforcement from other abused drugs, with potential relevance for broadly improving substance abuse treatment in women.